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Peripheral Blood DNA Methylation Signatures and Response to Tofacitinib in Moderate-to-severe Ulcerative Colitis. 外周血 DNA 甲基化特征与中重度溃疡性结肠炎患者对法西替尼的反应
IF 8.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-14 DOI: 10.1093/ecco-jcc/jjad129
Vincent Joustra, Andrew Y F Li Yim, Sara van Gennep, Ishtu Hageman, Tristan de Waard, Evgeni Levin, Peter Lauffer, Wouter de Jonge, Peter Henneman, Mark Löwenberg, Geert D'Haens

Introduction: Predictive biomarkers for treatment efficacy of ulcerative colitis [UC] treatments are lacking. Here, we performed a longitudinal study investigating the association and potential predictive power of genome-wide peripheral blood [PB] DNA methylation signatures and response to tofacitinib treatment in UC.

Methods: We recruited moderate-to-severe UC patients starting tofacitinib treatment, and measured PB DNA methylation profiles at baseline [T1], after 8 weeks [T2], and in a subset [n = 8] after a median of 20 weeks [T3] using the Illumina Infinium HumanMethylation EPIC BeadChip. After 8 weeks, we distinguished responders [R] from non-responders [NR] based on a centrally read endoscopic response [decrease in endoscopic Mayo score ≥1 or Ulcerative Colitis Endoscopic Index of Severity ≥2] combined with corticosteroid-free clinical and/or biochemical response. T1 PB samples were used for biomarker identification, and T2 and publicly available intraclass correlation [ICC] data were used for stability analyses. RNA-sequencing was performed to understand the downstream effects of the predictor CpG loci.

Results: In total, 16 R and 15 NR patients, with a median disease duration of 7 [4-12] years and overall comparable patient characteristics at baseline, were analysed. We identified a panel of 53 differentially methylated positions [DMPs] associated with response to tofacitinib [AUROC 0.74]. Most DMPs [77%] demonstrated both short- and long-term hyperstability [ICC ≥0.90], irrespective of inflammatory status. Gene expression analysis showed lower FGFR2 [pBH = 0.011] and LRPAP1 [pBH = 0.020], and higher OR2L13 [pBH = 0.016] expression at T1 in R compared with NR.

Conclusion: Our observations demonstrate the utility of genome-wide PB DNA methylation signatures to predict response to tofacitinib.

简介:目前尚缺乏预测溃疡性结肠炎(UC)疗效的生物标志物。在此,我们进行了一项纵向研究,调查全基因组外周血(PB)DNA甲基化特征与溃疡性结肠炎患者对法替尼治疗反应的相关性和潜在预测力:我们招募了开始接受托法替尼治疗的中重度 UC 患者,并使用 Illumina Infinium HumanMethylation EPIC BeadChip 在基线(T1)、8 周后(T2)和中位 20 周后(T3)测量了外周血 DNA 甲基化特征。8 周后,我们根据中心读取的内镜反应(内镜马约评分下降≥1 或 UCEIS ≥2)结合无皮质类固醇临床和/或生化反应,将反应者(R)与无反应者(NR)进行了分类。T1 PB样本用于生物标记物鉴定,而T2和公开的类内相关性(ICC)数据则用于稳定性分析。为了解预测CpG位点的下游效应,进行了RNA测序:共分析了 16 名 R 型和 15 名 NR 型患者,他们的中位病程为 7(4-12)年,基线时患者的总体特征相当。我们发现了53个与法西替尼应答相关的不同甲基化位点(DMPs)(AUROC 0.74)。大多数 DMPs(77%)显示出短期和长期的超稳定性(ICC ≥0.90),与炎症状态无关。基因表达分析显示,与NR相比,R患者在T1时FGFR2(pBH=0.011)和LRPAP1(pBH=0.020)表达较低,OR2L13(pBH=0.016)表达较高:我们的观察结果表明,全基因组 PB DNA 甲基化特征可用于预测对法替尼的反应。
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引用次数: 0
Whole Blood DNA Methylation Changes Are Associated with Anti-TNF Drug Concentration in Patients with Crohn's Disease. 克罗恩病患者全血 DNA 甲基化变化与抗肿瘤坏死因子药物浓度有关。
IF 8.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-14 DOI: 10.1093/ecco-jcc/jjad133
Simeng Lin, Eilis Hannon, Mark Reppell, Jeffrey F Waring, Nizar Smaoui, Valerie Pivorunas, Heath Guay, Neil Chanchlani, Claire Bewshea, Benjamin Y H Bai, Nicholas A Kennedy, James R Goodhand, Jonathan Mill, Tariq Ahmad

Background and aims: Anti-tumour necrosis factor [TNF] treatment failure in patients with inflammatory bowel disease [IBD] is common and frequently related to low drug concentrations. In order to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy, we sought to define epigenetic biomarkers in whole blood at baseline associated with anti-TNF drug concentrations at week 14.

Methods: DNA methylation from 1104 whole blood samples from 385 patients in the Personalised Anti-TNF Therapy in Crohn's disease [PANTS] study were assessed using the Illumina EPIC Beadchip [v1.0] at baseline and weeks 14, 30, and 54. We compared DNA methylation profiles in anti-TNF-treated patients who experienced primary non-response at week 14 if they were assessed at subsequent time points and were not in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 94], with patients who responded at week 14 and when assessed at subsequent time points were in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 93].

Results: Overall, between baseline and week 14, we observed 4999 differentially methylated positions [DMPs] annotated to 2376 genes following anti-TNF treatment. Pathway analysis identified 108 significant gene ontology terms enriched in biological processes related to immune system processes and responses. Epigenome-wide association [EWAS] analysis identified 323 DMPs annotated to 210 genes at baseline associated with higher anti-TNF drug concentrations at Week 14. Of these, 125 DMPs demonstrated shared associations with other common traits [proportion of shared CpGs compared with DMPs] including body mass index [23.2%], followed by C-reactive protein [CRP] [11.5%], smoking [7.4%], alcohol consumption per day [7.1%], and IBD type [6.8%]. EWAS of primary non-response to anti-TNF identified 20 DMPs that were associated with both anti-TNF drug concentration and primary non-response to anti-TNF with a strong correlation of the coefficients [Spearman's rho = -0.94, p <0.001].

Conclusion: Baseline DNA methylation profiles may be used as a predictor for anti-TNF drug concentration at week 14 to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy.

背景和目的:炎症性肠病(IBD)患者抗肿瘤坏死因子(anti-TNF)治疗失败很常见,而且经常与药物浓度低有关。为了在抗肿瘤坏死因子(anti-TNF)治疗初期确定哪些患者可从剂量优化中获益,我们试图确定基线全血中与第 14 周时抗肿瘤坏死因子药物浓度相关的表观遗传生物标志物:使用 Illumina EPIC Beadchip(v1.0)评估了克罗恩病个性化抗肿瘤坏死因子疗法(PANTS)研究中 385 名患者在基线、第 14 周、第 30 周和第 54 周的 1104 份全血样本中的 DNA 甲基化情况。我们比较了抗肿瘤坏死因子治疗患者的DNA甲基化图谱,这些患者在第14周出现原发性无应答,如果在随后的时间点进行评估,则在第30周或第54周没有缓解(英夫利昔单抗n=99,阿达木单抗n=94),与在第14周出现应答,在随后的时间点进行评估,则在第30周或第54周缓解的患者(英夫利昔单抗n=99,阿达木单抗n=93):总体而言,从基线到第14周,我们观察到4999个差异甲基化探针(DMPs)注释在抗肿瘤坏死因子治疗后的2376个基因上。全表观基因组关联(EWAS)分析发现,基线时注释在 210 个基因上的 323 个 DMPs 与第 14 周时较高的抗肿瘤坏死因子药物浓度有关。其中,125 个 DMPs 与其他共同特征(与 DMPs 相比,共享 CpGs 的比例)有共同关联,包括体重指数(23.2%),其次是 CRP(11.5%)、吸烟(7.4%)、每日饮酒量(7.1%)和 IBD 类型(6.8%)。抗肿瘤坏死因子原发性无应答EWAS确定了20个与抗肿瘤坏死因子药物浓度和抗肿瘤坏死因子原发性无应答相关的DMPs,其系数具有很强的相关性(Spearman's rho = -0.94,p < 0.001):基线DNA甲基化图谱可用作第14周抗TNF药物浓度的预测因子,以识别可能在抗TNF治疗初期从剂量优化中获益的患者。
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引用次数: 0
6-Mercaptopurine in ulcerative colitis: the potential of upfront dosing with allopurinol. 溃疡性结肠炎患者使用 6-巯基嘌呤:与别嘌呤醇同时使用的潜力。
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-01 DOI: 10.1093/ecco-jcc/jjad150
Steven Trinh, Bridgette Andrew, Abhinav Vasudevan
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引用次数: 0
Prevalence of Hepatobiliary Manifestations in Inflammatory Bowel Disease: A GRADE Assessed Systematic Review and Meta-Analysis of more than 1.7 Million Patients. 炎症性肠病肝胆表现的患病率:对 170 多万患者进行 GRADE 评估的系统回顾和元分析
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-01 DOI: 10.1093/ecco-jcc/jjad157
Alireza Beheshti Maal, Mohammad Amin Shahrbaf, Bahareh Sadri, Nikoo Hossein-Khannazer, Mohammad Ali Mansournia, Massoud Vosough

Background and aims: Inflammatory bowel disease [IBD] comprises an immune-mediated group of chronic gastrointestinal disorders. Patients with IBD may experience extraintestinal manifestations, such as hepatobiliary complications. This meta-analysis aims to assess the prevalence of different hepatic manifestations in IBD patients.

Methods: For this systematic review and meta-analysis, PubMed, Scopus, Web of Science, and Embase were searched until July 20, 2022, by specifying keywords for IBD, hepatic manifestations, and study type. Full texts of cohort studies in English that examined the prevalence of different hepatic manifestations were included in this study. The primary outcome was the overall prevalence of hepatic manifestations in IBD patients. For the statistical analysis, a proportion by random effect model meta-analysis was performed. The registration number for the protocol of this study in PROSPERO is CRD42022369595.

Results: From the 4421 articles retrieved from the primary search, 118 met the inclusion criteria and were included in the final analysis. After a pooled analysis of 1 729 128 patients, the overall prevalence of hepatic manifestations was 3.49% (95% confidence interval [CI]: 3.31-3.68%; I2: 99.55%). The pooled prevalence of non-alcoholic fatty liver disease in 228 216 patients was 26.1% [95% CI: 22.1-30.2%; I2: 99.018%]. After pooled analysis of 9642 patients, the prevalence of primary sclerosing cholangitis was 1.67% [95% CI: 1.47-1.88%; I2: 99.10%]. The pooled prevalence of biliary stones was 4.1% [95% CI: 3.6-4.7%; I2: 97.43%]. Autoimmune hepatitis (0.51% [95% CI: 0.26-0.75%]; I2: 85.36%) and portal vein thrombosis (0.21% [95% CI: 0.08-0.33%]; I2: 97.95%) are considered as rare manifestations.

Conclusion: This study summarizes the prevalence and importance of different hepatic manifestations in IBD patients. These findings are crucial for the management of extraintestinal manifestations, especially hepatic manifestations, in IBD patients.

背景和目的:炎症性肠病(IBD)是一组由免疫介导的慢性胃肠道疾病。IBD 患者可能会出现肠道外表现,如肝胆并发症。本荟萃分析旨在评估 IBD 患者不同肝脏表现的患病率:为了进行本系统综述和荟萃分析,我们检索了 PubMed、Scopus、Web of Science 和 Embase,检索截止日期为 2022 年 7 月 20 日,检索时注明了 IBD、肝脏表现和研究类型等关键词。本研究纳入了研究不同肝脏表现患病率的英文队列研究全文。主要结果是 IBD 患者肝脏表现的总体患病率。统计分析采用随机效应模型荟萃分析法。本研究方案在 PROSPERO 的注册号为 CRD42022369595:从主要搜索中检索到的 4421 篇文章中,有 118 篇符合纳入标准并被纳入最终分析。在对 1 729 128 名患者进行汇总分析后,肝脏表现的总患病率为 3.49%(95% 置信区间 [CI]:3.31-3.68%;I2:99.55%)。在 228 216 名患者中,非酒精性脂肪肝的汇总患病率为 26.1% [95% CI:22.1-30.2%;I2:99.018%]。对 9642 名患者进行汇总分析后,原发性硬化性胆管炎的患病率为 1.67% [95% CI:1.47-1.88%;I2:99.10%]。胆道结石的汇总患病率为 4.1% [95% CI:3.6-4.7%;I2:97.43%]。自身免疫性肝炎(0.51% [95% CI:0.26-0.75%];I2:85.36%)和门静脉血栓形成(0.21% [95% CI:0.08-0.33%];I2:97.95%)被认为是罕见表现:本研究总结了IBD患者不同肝脏表现的患病率和重要性。结论:本研究总结了 IBD 患者不同肝脏表现的患病率和重要性,这些发现对于处理 IBD 患者的肠外表现,尤其是肝脏表现至关重要。
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引用次数: 0
Mitigating the Risk of Tofacitinib-induced Adverse Events in the Elderly Population with Ulcerative Colitis. 降低溃疡性结肠炎老年人群中托法替尼引发不良事件的风险
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-01 DOI: 10.1093/ecco-jcc/jjad158
Anna Viola, Raffaele Li Voti, Chiara Bivacqua, Clara De Francesco, Marco Muscianisi, Giuseppe Costantino, Walter Fries

Background and aims: Older patients with ulcerative colitis treated with tofacitinib are at risk for major cardiovascular events, thromboembolism, herpes zoster, and malignancies and, accordingly, its use is limited by the regulatory authorities. The aim of the present study was to evaluate the occurrence of adverse events and potential preventive measures.

Methods: We retrospectively evaluated patients treated with tofacitinib, divided into two groups according to comorbidities and age. Patient- and disease-related variables were recorded [primary non-response, loss of response, and persistence], together with deviations from the recommended induction regimen, ie, dose reduction, and concomitant treatments with anti-thrombotic therapy.

Results: The age-adjusted Charlson comorbidity index of Group 1 [n = 30] was ≥2 and that of Group 2 [n = 37] was ≤ 1. No differences were observed for primary or secondary treatment failures. Both groups achieved comparable steroid-free remission rates at 12 months [53% and 46%, respectively]. Herpes zoster occurred in two patients per group, and no more cases occurred after strict recombinant zoster vaccination. No major cardiovascular event or thromboembolism was registered. Half of patients in Group 1 were treated with a reduced induction dose of 5 mg twice daily and 47% were on concomitant anti-thrombotic therapy. Malignancies were registered in two patients from Group 1 and one patient from Group 2.

Conclusions: Modulation of induction dose and anti-thrombotic therapy may have contributed to prevent cardiological events and thromboembolism. The introduction of zoster vaccine virtually eliminated zoster risk after the first cases. Potential malignancies deserve a careful work-up of older patients before treatment start.

背景和目的:接受托法替尼治疗的老年溃疡性结肠炎患者存在发生重大心血管事件、血栓栓塞、带状疱疹和恶性肿瘤的风险,因此监管机构限制其使用。本研究旨在评估不良事件的发生情况和潜在的预防措施:我们对接受托法替尼治疗的患者进行了回顾性评估,根据合并症和年龄分为两组。我们记录了与患者和疾病相关的变量[原发性无应答、应答丧失和持续性],以及偏离推荐诱导方案的情况(即剂量减少)和同时接受抗血栓治疗的情况:第1组[n = 30]的年龄调整后Charlson合并症指数≥2,第2组[n = 37]的年龄调整后Charlson合并症指数≤1。初治和复治失败率无差异。两组患者在12个月后的无类固醇缓解率相当[分别为53%和46%]。每组有两名患者出现带状疱疹,严格接种重组带状疱疹疫苗后没有再出现病例。没有发生重大心血管事件或血栓栓塞。第 1 组的半数患者接受了每日两次、每次 5 毫克的减量诱导治疗,47% 的患者同时接受了抗血栓治疗。第一组和第二组分别有两名和一名患者出现恶性肿瘤:调整诱导剂量和抗血栓治疗可能有助于预防心脏病和血栓栓塞。带状疱疹疫苗的引入几乎消除了首例患者的带状疱疹风险。老年患者在开始治疗前应仔细检查是否有潜在的恶性肿瘤。
{"title":"Mitigating the Risk of Tofacitinib-induced Adverse Events in the Elderly Population with Ulcerative Colitis.","authors":"Anna Viola, Raffaele Li Voti, Chiara Bivacqua, Clara De Francesco, Marco Muscianisi, Giuseppe Costantino, Walter Fries","doi":"10.1093/ecco-jcc/jjad158","DOIUrl":"10.1093/ecco-jcc/jjad158","url":null,"abstract":"<p><strong>Background and aims: </strong>Older patients with ulcerative colitis treated with tofacitinib are at risk for major cardiovascular events, thromboembolism, herpes zoster, and malignancies and, accordingly, its use is limited by the regulatory authorities. The aim of the present study was to evaluate the occurrence of adverse events and potential preventive measures.</p><p><strong>Methods: </strong>We retrospectively evaluated patients treated with tofacitinib, divided into two groups according to comorbidities and age. Patient- and disease-related variables were recorded [primary non-response, loss of response, and persistence], together with deviations from the recommended induction regimen, ie, dose reduction, and concomitant treatments with anti-thrombotic therapy.</p><p><strong>Results: </strong>The age-adjusted Charlson comorbidity index of Group 1 [n = 30] was ≥2 and that of Group 2 [n = 37] was ≤ 1. No differences were observed for primary or secondary treatment failures. Both groups achieved comparable steroid-free remission rates at 12 months [53% and 46%, respectively]. Herpes zoster occurred in two patients per group, and no more cases occurred after strict recombinant zoster vaccination. No major cardiovascular event or thromboembolism was registered. Half of patients in Group 1 were treated with a reduced induction dose of 5 mg twice daily and 47% were on concomitant anti-thrombotic therapy. Malignancies were registered in two patients from Group 1 and one patient from Group 2.</p><p><strong>Conclusions: </strong>Modulation of induction dose and anti-thrombotic therapy may have contributed to prevent cardiological events and thromboembolism. The introduction of zoster vaccine virtually eliminated zoster risk after the first cases. Potential malignancies deserve a careful work-up of older patients before treatment start.</p>","PeriodicalId":15547,"journal":{"name":"Journal of Crohns & Colitis","volume":" ","pages":"488-491"},"PeriodicalIF":8.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10223849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Temporary Faecal Diversion for Refractory Perianal and/or Distal Colonic Crohn's Disease in the Biologic Era: An Updated Systematic Review with Meta-analysis. 生物时代难治性肛周和/或结肠远端克罗恩病的临时粪便转流治疗:最新系统综述与 Meta 分析。
IF 8.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-01 DOI: 10.1093/ecco-jcc/jjad159
Michael Jew, Joseph Meserve, Samuel Eisenstein, Vipul Jairath, Jeffrey McCurdy, Siddharth Singh

Background and aims: We evaluated short- and long-term outcomes of temporary faecal diversion [FD] for management of refractory Crohn's disease [CD], focusing on outcomes in the biologic era.

Methods: Through a systematic literature review until March 15, 2023, we identified 33 studies [19 conducted in the biologic era] that evaluated 1578 patients with perianal and/or distal colonic CD who underwent temporary FD [with intent of restoring bowel continuity] and reported long-term outcomes [primary outcome: successful restoration of bowel continuity, defined as remaining ostomy-free after reconnection at a minimum of 6 months after diversion or at the end of follow-up]. We calculated pooled rates (with 95% confidence interval [CI]) using random effects meta-analysis, and examined factors associated with successful restoration of bowel continuity.

Results: Overall, 61% patients [95% CI, 52-68%; 50% in biologic era] experienced clinical improvement after FD. Stoma takedown was attempted in 34% patients [28-41%; 37% in biologic era], 6-18 months after diversion. Among patients where bowel restoration was attempted, 63% patients [54-71%] had successful restoration of bowel continuity, and 26% [20-34%] required re-diversion. Overall, 21% patients [17-27%; 24% in biologic era] who underwent FD were successfully restored; 34% patients [30-39%; 31% in biologic era] required proctectomy with permanent ostomy. On meta-regression, post-diversion biologic use and absence of proctitis was associated with successful bowel restoration after temporary FD in contemporary studies.

Conclusion: In the biologic era, temporary FD for refractory perianal and/or distal colonic CD improves symptoms in half the patients, and bowel continuity can be successfully restored in a quarter of patients.

背景和目的:我们评估了用于治疗难治性克罗恩病(CD)的临时粪便转流术(FD)的短期和长期疗效,重点关注生物制剂时代的疗效:通过对截至 2023 年 3 月 15 日的文献进行系统性回顾,我们确定了 33 项研究(19 项在生物制剂时代进行),这些研究评估了 1578 名肛周和/或远端结肠 CD 患者,这些患者接受了临时粪便转流术[旨在恢复肠道连续性],并报告了长期结果[主要结果:成功恢复肠道连续性,定义为转流后至少 6 个月或随访结束时重新连接后仍无造口]。我们使用随机效应荟萃分析法计算了汇总率(含 95% 置信区间 [CI]),并研究了成功恢复肠道连续性的相关因素:总体而言,61%的患者[95% CI,52%-68%;生物时代为 50%]在接受 FD 后临床症状有所改善。34%的患者[28-41%;生物制剂时代为 37%]在肠道转流术后 6-18 个月尝试过拆开造口。在尝试恢复肠道功能的患者中,63% 的患者[54-71%]成功恢复了肠道连续性,26% 的患者[20-34%]需要再次转流。总体而言,21%[17-27%;生物制剂时代为 24%]接受 FD 的患者成功恢复了肠道功能;34%[30-39%;生物制剂时代为 31%]的患者需要进行直肠切除术和永久性造口术。元回归结果显示,在当代研究中,转流后使用生物制剂和无直肠炎与临时切除术后成功恢复肠道功能有关:结论:在生物制剂时代,针对难治性肛周和/或远端结肠 CD 的临时 FD 可改善半数患者的症状,四分之一的患者可成功恢复肠道连续性。
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引用次数: 0
Prospective Observational Evaluation of the Time-Dependency of Adalimumab Immunogenicity and Drug Concentration in Ulcerative Colitis Patients: the POETIC II Study. 阿达木单抗免疫原性和药物浓度对溃疡性结肠炎患者时间依赖性的前瞻性观察评估:POETIC II研究。
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-03-01 DOI: 10.1093/ecco-jcc/jjad156
Sivan Harnik, Chaya M Abitbol, Ola Haj Natour, Miri Yavzori, Ella Fudim, Orit Picard, Timna Naftali, Efrat Broide, Ayal Hirsch, Limor Selinger, Eyal Shachar, Doron Yablecovitch, Ahmad Albshesh, Daniel Coscas, Uri Kopylov, Rami Eliakim, Shomron Ben-Horin, Bella Ungar

Background and aims: Home self-injection of the human anti-tumour necrosis alpha [anti-TNFα] monoclonal adalimumab complicates prospective serial-sampling studies. Although a recent study examined adalimumab levels and immunogenicity in Crohn's disease [CD] patients, prospective real-world data from ulcerative colitis [UC] patients are lacking.

Methods: A three-monthly home-visit programme from induction was established prospectively for UC patients. Clinical scores were determined at each visit, and sera were obtained for assessment of drug and anti-adalimumab antibody levels. Calprotectin was measured using a smartphone-based app. This cohort was compared to a parallel prospective cohort of adalimumab-treated CD patients [POETIC1].

Results: Fifty UC patients starting adalimumab [median follow-up 28 weeks] were compared to 98 adalimumab-treated CD patients [median follow-up 44 weeks]. Only 11/50 UC patients [22%] continued treatment to the end of the follow-up compared with 50/98 [51%] CD patients (odds ratio [OR] = 0.27, p = 0.001). Loss of response was significantly more common in UC patients [OR = 3.2, p = 0.001]. Seventeen patients [34%] in the UC cohort developed anti-adalimumab antibodies, 9/17 [52.9%] as early as week 2. There was no difference between patient cohorts in the overall development of anti-adalimumab antibodies [34% vs 30.6%, respectively, OR = 1.67, p = 0.67], nor was there a difference in early immunogenicity [OR = 1.39, p = 0.35]. There was no difference in low drug levels [<3 µg/mL] between the two cohorts [OR = 0.87, p = 0.83].

Conclusions: Loss of response to adalimumab therapy was significantly more common in the UC compared to the CD cohort and was driven by a higher rate of non-immunogenic, pharmacodynamic parameters.

背景和目的:在家自行注射人抗TNFα单克隆阿达木单抗使前瞻性系列抽样研究变得复杂。尽管最近的一项研究检测了克罗恩病患者的阿达木单抗水平和免疫原性,但缺乏溃疡性结肠炎患者的前瞻性真实世界数据。方法:前瞻性地为溃疡性结肠炎患者制定了一个从诱导开始为期三个月的家访计划。在每次就诊时测定临床评分,并获得血清以评估药物和抗阿达木单抗抗体水平。使用基于智能手机的应用程序测量钙卫蛋白。该队列与阿达木单抗治疗的克罗恩病患者的平行前瞻性队列(POETIC1)进行了比较。只有11/50名溃疡性结肠炎患者(22%)继续治疗至随访结束,而克罗恩病患者中有50/98名(51%)滞留(OR=0.27,P=0.001)。反应丧失在溃疡性结肠炎中更为常见(P=0.001,OR=3.2)。溃疡性结肠炎队列中有17名患者(34%)产生了抗阿达木单抗抗体;9/17(52.9%)。抗阿达木单抗抗体的总体发展在患者队列之间没有差异(分别为34%和30.6%,OR=1.67,P=0.67),早期免疫原性也没有差异(OR=1.39,P=0.35)。低药物水平没有差异(结论:与克罗恩病队列相比,阿达木单抗治疗的反应丧失在溃疡性结肠炎中更为常见,并且是由更高的非免疫原性药效学参数率驱动的。
{"title":"Prospective Observational Evaluation of the Time-Dependency of Adalimumab Immunogenicity and Drug Concentration in Ulcerative Colitis Patients: the POETIC II Study.","authors":"Sivan Harnik, Chaya M Abitbol, Ola Haj Natour, Miri Yavzori, Ella Fudim, Orit Picard, Timna Naftali, Efrat Broide, Ayal Hirsch, Limor Selinger, Eyal Shachar, Doron Yablecovitch, Ahmad Albshesh, Daniel Coscas, Uri Kopylov, Rami Eliakim, Shomron Ben-Horin, Bella Ungar","doi":"10.1093/ecco-jcc/jjad156","DOIUrl":"10.1093/ecco-jcc/jjad156","url":null,"abstract":"<p><strong>Background and aims: </strong>Home self-injection of the human anti-tumour necrosis alpha [anti-TNFα] monoclonal adalimumab complicates prospective serial-sampling studies. Although a recent study examined adalimumab levels and immunogenicity in Crohn's disease [CD] patients, prospective real-world data from ulcerative colitis [UC] patients are lacking.</p><p><strong>Methods: </strong>A three-monthly home-visit programme from induction was established prospectively for UC patients. Clinical scores were determined at each visit, and sera were obtained for assessment of drug and anti-adalimumab antibody levels. Calprotectin was measured using a smartphone-based app. This cohort was compared to a parallel prospective cohort of adalimumab-treated CD patients [POETIC1].</p><p><strong>Results: </strong>Fifty UC patients starting adalimumab [median follow-up 28 weeks] were compared to 98 adalimumab-treated CD patients [median follow-up 44 weeks]. Only 11/50 UC patients [22%] continued treatment to the end of the follow-up compared with 50/98 [51%] CD patients (odds ratio [OR] = 0.27, p = 0.001). Loss of response was significantly more common in UC patients [OR = 3.2, p = 0.001]. Seventeen patients [34%] in the UC cohort developed anti-adalimumab antibodies, 9/17 [52.9%] as early as week 2. There was no difference between patient cohorts in the overall development of anti-adalimumab antibodies [34% vs 30.6%, respectively, OR = 1.67, p = 0.67], nor was there a difference in early immunogenicity [OR = 1.39, p = 0.35]. There was no difference in low drug levels [<3 µg/mL] between the two cohorts [OR = 0.87, p = 0.83].</p><p><strong>Conclusions: </strong>Loss of response to adalimumab therapy was significantly more common in the UC compared to the CD cohort and was driven by a higher rate of non-immunogenic, pharmacodynamic parameters.</p>","PeriodicalId":15547,"journal":{"name":"Journal of Crohns & Colitis","volume":" ","pages":"341-348"},"PeriodicalIF":8.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10570413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Race and Ethnic Representation in Crohn's Disease Trials of Biologic and Small Molecule Medications: A Systematic Review and Meta-analysis. 克罗恩病生物制剂和小分子药物试验中的种族和民族代表性:系统回顾与元分析》。
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-02-26 DOI: 10.1093/ecco-jcc/jjad138
Matt Pelton, Paddy Ssentongo, Ashley Sun, Destin Groff, Shannon Dalessio, Kofi Clarke

Background and aims: Randomised controlled trials historically under-represent marginalised racial and ethnic populations. As incidence and prevalence of Crohn's disease in these groups rise, it is important to characterise their inclusion in randomised controlled trials on first-line and pipe-line medications.

Methods: PubMed was searched systematically for randomised controlled trials of biologic and small molecule inhibitor [SMI] medications, with a primary outcome related to efficacy following PRISMA guidelines. We used descriptive statistics to summarise demographic variables and meta-regression analyses to estimate temporal trends in racial inclusion.

Results: More than a half of trials did not report any racial/ethnic demographics [53.7%] and several reported racial demographics for only one race [20.9%]. When racial data were reported, Whites made up 90.2% of participants. Percentages of Black, Asian, Native American/Pacific Islander, and participants considered 'Other' averaged 2.9%, 11.6%, 0.5%, and 1.6% out of the total sample sizes of 3901, 3742, 828 and 4027, respectively. Proportional representation of White participants decreased over time [p <0.01] and proportional representation of Asian participants increased over time [p = 0.047]. In ordinal logistic regression, mean year of trial enrolment significantly increased the number of racial groups reported [p <0.001].

Conclusions: Half of published randomised controlled trials in Crohn's disease contain no racial or ethnic demographics, and the remaining often only have limited inclusion of Black, Native American/Pacific Islander, and Hispanic patients. Further work should characterise representation in observational and prospective trials. Researchers should work to: 1] increase reporting of racial and ethnic demographics; and 2] improve recruitment and retention of marginalised populations.

背景和目的:历史上,随机对照试验对边缘化种族和民族人群的代表性不足。随着这些群体中克罗恩病发病率和患病率的上升,将他们纳入一线和二线药物的随机对照试验非常重要:按照 PRISMA 指南,我们在 PubMed 上系统检索了生物制剂和小分子抑制剂 [SMI] 药物的随机对照试验,试验的主要结果与疗效有关。我们使用描述性统计来总结人口统计学变量,并使用元回归分析来估计种族纳入的时间趋势:结果:一半以上的试验未报告任何种族/族裔人口统计数据[53.7%],一些试验仅报告了一个种族的人口统计数据[20.9%]。在报告种族数据时,白人占参与者的 90.2%。在 3901、3742、828 和 4027 个样本中,黑人、亚裔、美国原住民/太平洋岛民和被视为 "其他 "的参与者的平均比例分别为 2.9%、11.6%、0.5% 和 1.6%。随着时间的推移,白人参与者的比例有所下降[p 结论:在已发表的克罗恩病随机对照试验中,有一半不包含种族或族裔人口统计,其余的试验通常只有限地纳入了黑人、美国原住民/太平洋岛民和西班牙裔患者。进一步的工作应确定观察性和前瞻性试验中的代表性特征。研究人员应努力1] 增加种族和民族人口统计数据的报告;以及 2] 改善边缘化人群的招募和保留。
{"title":"Race and Ethnic Representation in Crohn's Disease Trials of Biologic and Small Molecule Medications: A Systematic Review and Meta-analysis.","authors":"Matt Pelton, Paddy Ssentongo, Ashley Sun, Destin Groff, Shannon Dalessio, Kofi Clarke","doi":"10.1093/ecco-jcc/jjad138","DOIUrl":"10.1093/ecco-jcc/jjad138","url":null,"abstract":"<p><strong>Background and aims: </strong>Randomised controlled trials historically under-represent marginalised racial and ethnic populations. As incidence and prevalence of Crohn's disease in these groups rise, it is important to characterise their inclusion in randomised controlled trials on first-line and pipe-line medications.</p><p><strong>Methods: </strong>PubMed was searched systematically for randomised controlled trials of biologic and small molecule inhibitor [SMI] medications, with a primary outcome related to efficacy following PRISMA guidelines. We used descriptive statistics to summarise demographic variables and meta-regression analyses to estimate temporal trends in racial inclusion.</p><p><strong>Results: </strong>More than a half of trials did not report any racial/ethnic demographics [53.7%] and several reported racial demographics for only one race [20.9%]. When racial data were reported, Whites made up 90.2% of participants. Percentages of Black, Asian, Native American/Pacific Islander, and participants considered 'Other' averaged 2.9%, 11.6%, 0.5%, and 1.6% out of the total sample sizes of 3901, 3742, 828 and 4027, respectively. Proportional representation of White participants decreased over time [p <0.01] and proportional representation of Asian participants increased over time [p = 0.047]. In ordinal logistic regression, mean year of trial enrolment significantly increased the number of racial groups reported [p <0.001].</p><p><strong>Conclusions: </strong>Half of published randomised controlled trials in Crohn's disease contain no racial or ethnic demographics, and the remaining often only have limited inclusion of Black, Native American/Pacific Islander, and Hispanic patients. Further work should characterise representation in observational and prospective trials. Researchers should work to: 1] increase reporting of racial and ethnic demographics; and 2] improve recruitment and retention of marginalised populations.</p>","PeriodicalId":15547,"journal":{"name":"Journal of Crohns & Colitis","volume":" ","pages":"204-211"},"PeriodicalIF":8.0,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10389310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Transcriptomic Profiling and Cellular Composition of Creeping Fat in Crohn's disease. 克罗恩病爬行脂肪的转录组分析和细胞组成
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-02-26 DOI: 10.1093/ecco-jcc/jjad141
Kyuwon Kim, Sojung Park, Yoonho Lee, Jiwon Baek, Yongjae Kim, Sung Wook Hwang, Jong Lyul Lee, Sang Hyoung Park, Suk-Kyun Yang, Buhm Han, Kyuyoung Song, Yong Sik Yoon, Ho-Su Lee, Byong Duk Ye

Background and aims: Creeping fat [CF] is a poorly understood feature of Crohn's disease [CD], characterized by the wrapping of mesenteric adipose tissue [MAT] around the inflamed intestine. The aim of this study was to investigate the transcriptional profile and compositional features of CF.

Methods: We collected 59 MAT samples: 23 paired samples from patients with CD (CF [CD-CF] and MAT around the uninflamed intestine [CD-MAT]) and 13 MAT samples from non-CD patients [Con-MAT]. Differentially expressed gene [DEG], functional pathway, cell deconvolution, and gene co-expression network analyses were performed.

Results: By comparing three different MAT samples, we identified a total of 529 DEGs [|log2FoldChange| > 1.5; false discovery rate < 0.05]. Of these, 323 genes showed an incremental pattern from Con-MAT to CD-MAT, and to CD-CF, while 105 genes displayed a decremental pattern. Genes with an incremental pattern were related to immune cell responses, including B- and T-cell activation, while genes with a decremental pattern were involved in cell trafficking and migration. Cell deconvolution analysis revealed significant changes in cellular composition between the CD-CF and Con-MAT groups, with increased proportions of B-cells/plasma cells [p = 1.16 × 10-4], T-cells [p = 3.66 × 10-3], and mononuclear phagocytes [p = 3.53 × 10-2] in the CD-CF group. In contrast, only the B-cell/plasma cell component showed a significant increase [p = 1.62 × 10-2] in the CD-MAT group compared to Con-MAT.

Conclusion: The distinct transcriptional profiles and altered cellular components of each MAT found in our study provide insight into the mechanisms behind CF and highlight its possible role in the pathogenesis of CD.

背景和目的:蠕动脂肪(CF)是克罗恩病(CD)的一个鲜为人知的特征,其特点是肠系膜脂肪组织(MAT)包裹着发炎的肠道。本研究的目的是调查爬行脂肪的转录谱和组成特征:我们收集了 59 份肠系膜脂肪组织样本:方法:我们收集了 59 份 MAT 样本:23 份来自 CD 患者(CF [CD-CF] 和未发炎肠道周围的 MAT [CD-MAT])的配对样本和 13 份来自非 CD 患者的 MAT 样本 [Con-MAT]。对差异表达基因(DEG)、功能通路、细胞解旋和基因共表达网络进行了分析:结果:通过比较三个不同的 MAT 样本,我们共发现了 529 个 DEGs [|log2FoldChange| > 1.5; false discovery rate < 0.05]。其中,323 个基因显示出从 Con-MAT 到 CD-MAT 再到 CD-CF 的递增模式,而 105 个基因显示出递减模式。呈递增模式的基因与免疫细胞反应有关,包括 B 细胞和 T 细胞的活化,而呈递减模式的基因则与细胞贩运和迁移有关。细胞解旋分析显示,CD-CF 组和 Con-MAT 组的细胞组成发生了显著变化,CD-CF 组中 B 细胞/浆细胞[p = 1.16 × 10-4]、T 细胞[p = 3.66 × 10-3]和单核吞噬细胞[p = 3.53 × 10-2]的比例增加。相比之下,CD-MAT 组与 Con-MAT 组相比,只有 B 细胞/浆细胞成分显著增加 [p = 1.62 × 10-2]:结论:我们的研究发现,每种 MAT 都有不同的转录谱和细胞成分改变,这有助于深入了解 CF 背后的机制,并突出了其在 CD 发病机制中可能扮演的角色。
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引用次数: 0
Efficacy and Safety of Approximately 3 Years of Continuous Ozanimod in Moderately to Severely Active Ulcerative Colitis: Interim Analysis of the True North Open-label Extension. 中度至重度活动性溃疡性结肠炎患者持续服用奥扎莫德约 3 年的疗效和安全性:真北 "开放标签推广项目中期分析。
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-02-26 DOI: 10.1093/ecco-jcc/jjad146
Silvio Danese, Remo Panaccione, Maria T Abreu, David T Rubin, Subrata Ghosh, Axel Dignass, Anita Afzali, Douglas C Wolf, Michael V Chiorean, Severine Vermeire, Anjali Jain, Lorna Charles, Garrett Lawlor, Mark T Osterman, Hsiuanlin Wu, James B Canavan, AnnKatrin Petersen, Jean-Frederic Colombel, Miguel Regueiro

Backgrounds and aims: This interim analysis from the True North open-label extension [OLE] study examines efficacy and safety of approximately 3 years of continuous ozanimod treatment in patients with moderately to severely active ulcerative colitis.

Methods: Clinical responders after 52 weeks of ozanimod during the phase 3 True North study, who continued treatment in the OLE, were evaluated. Efficacy, including endoscopic and histological endpoints, was assessed during the OLE for approximately 2 additional years through OLE Week 94, using observed case [OC] and nonresponder imputation [NRI] analyses. Adverse events were monitored from True North baseline through OLE data cutoff and expressed as exposure-adjusted incidence rates.

Results: This analysis included 131 patients; 54% had achieved corticosteroid-free remission at True North Week 52. In OC analyses, clinical response, clinical remission, and corticosteroid-free remission were achieved by 91.4%, 69.1%, and 67.9% of patients, respectively, at OLE Week 94 [146 weeks of total treatment]. Similarly, endoscopic improvement, histological remission, and mucosal healing were achieved by 73.3%, 67.3%, and 56.3% of patients, respectively, at OLE Week 94. Efficacy rates were lower using NRI analyses, but maintenance of efficacy was demonstrated through OLE Week 94. No new safety signals emerged from this analysis. Serious infections, malignancy, cardiovascular events, and hepatic events occurred infrequently.

Conclusions: Among patients who achieved clinical response after 1 year of ozanimod treatment during True North, a high percentage sustained clinical and mucosal efficacy over 2 additional years in the OLE. No new safety signals were observed with long-term ozanimod use.

背景和目的:这项 "True North "开放标签扩展[OLE]研究的中期分析考察了中度至重度活动性溃疡性结肠炎患者连续接受奥扎莫德治疗约 3 年的疗效和安全性:方法: 对在 "真实北方 "三期研究中接受奥扎莫德治疗 52 周后,在 OLE 中继续接受治疗的临床应答者进行评估。在 OLE 期间,使用观察病例 [OC] 和非应答者归因 [NRI] 分析法,在 OLE 第 94 周之前的约 2 年时间内评估疗效,包括内镜和组织学终点。从 "真北 "基线到 OLE 数据截止期间对不良事件进行监测,并以暴露调整后的发病率表示:该分析包括 131 名患者;54% 的患者在 "真实北方 "第 52 周时获得了无皮质类固醇缓解。在 OC 分析中,91.4%、69.1% 和 67.9% 的患者在 OLE 第 94 周[共治疗 146 周]时获得了临床应答、临床缓解和无皮质类固醇缓解。同样,在OLE第94周时,分别有73.3%、67.3%和56.3%的患者实现了内镜改善、组织学缓解和粘膜愈合。使用 NRI 分析的有效率较低,但在 OLE 第 94 周时疗效得以维持。该分析未发现新的安全性信号。严重感染、恶性肿瘤、心血管事件和肝脏事件发生率较低:结论:在 "真北方 "期间接受奥扎莫德治疗 1 年后获得临床应答的患者中,有很高比例的患者在 OLE 治疗的另外 2 年中保持了临床和粘膜疗效。长期使用奥扎莫德未发现新的安全信号。
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引用次数: 0
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Journal of Crohns & Colitis
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